The placenta is a remarkable fetal support system. It functions as the fetal lung and is responsible for all gas transfer from the mother to the fetus. The placenta controls excretory functions, water balance, and pH regulation as the fetal kidney. It acts as the fetal gut by performing catabolic and resorptive functions. It also performs most synthetic and secretory functions of the endocrine glands and liver. Finally, the placenta provides hematopoiesis of the bone marrow during the early stages of pregnancy, controls heat transfer of the skin, and performs immunological functions to a largely unknown degree.
Disruptions in the maternal circulation to the placenta, and thus in the fetal circulation, can result in intrauterine growth retardation ("IUGR") or even fetal death. IUGR may be a direct effect of hypoxia upon fetal tissues or caused by a reduction in the supply of nutrients to the fetus. The importance of uteroplacental blood flow in the nutrition of both the maternal and fetal placenta has been shown by observations of placentas in animal models and in fetuses that have not survived IUGR. Histological characteristics used by investigators to describe placental insufficiency have been correlated to the consequences of fetal nutritional deprivation.
As many as 250,000 babies are born each year that weigh less than 2,500 grams and are thus described as low birth weight (LBW) infants. These babies are 40 times more likely to die in the neonatal period. For the segment of newborns weighing less than 1,500 grams, the relative risk is 200 times greater. In 1990, the hospital-related costs of caring for all LBW infants during the neonatal period totaled more than two billion dollars. LBW infants make up only about 7% of all births, but the costs associated with their care in 1990 represented about 57% of the costs incurred for all newborns.
Even when LBW infants survive, about half are categorized as "small for their gestational age" ("SGA"). These SGA infants are significantly compromised in utero and lack the resilience normally seen for infants at their gestational age during labor, delivery and the neonatal period. Sometimes, infants are even classified as both premature and SGA, and these babies constitute a significant minority that have an even higher morbidity rate. Epidemiological studies have shown that it is the relative weight of the infant, rather than the length of gestation, that is the primary factor affecting an infant's chances of survival.
Additionally, pathological alterations in the placental vasculature have been correlated to preeclampsia, a disease affecting 5 to 10% of pregnant women. Left undetected, women with preeclampsia are at risk for maternal death, fetal IUGR and fetal death.
There has been a need to reduce perinatal morbidity and mortality by significantly reducing the incidence of both the SGA fetus and the LBW fetus. To this end, there is a need to protect human fetuses that are at risk by assuring a maternal environment that can support fetal nutritional needs.
One way to do this is to attempt to visualize the maternal circulation in the placenta in a sonogram. However, current methods that employ ultrasound techniques including Doppler flow to examine intervillous blood flow of the mother's circulation in the placenta have not been entirely successful. This is because current ultrasound techniques are limited by the low flow state, the relatively small target spaces, and the lack of spatial resolution.
Contrast media have been suggested to detect aspects of flow and tissue perfusion in other situations, most frequently, the heart or the organs of the gastrointestinal tract, but also including the cardiovascular system, liver, spleen, kidney, pancreas, tumor tissue, muscle tissue, or bodily fluids such as blood. See, for example, Unger, U.S. Pat. No. 5,209,720 issued May 11, 1993 (tumor tissue, muscle tissue or blood fluid), and Unger et al., U.S. Pat. No. 5,228,446 issued Jul. 20, 1993 (liver, spleen, kidneys, heart, vasculature, diseased tissue and blood flow).
More specifically, Erbel et al., U.S. Pat. No. 5,205,287 issued 27 Apr. 1993, states that certain ultrasonic contrast media can be used to visualize the blood flow in the right ventricle or left side of the heart, the myocardium, the liver, spleen, kidney or brain. Further, the contrast media of Erbel et al. are described as also suitable for the visualization of the urinary bladder, ureter, uterus or vagina. Two U.S. patents (Rasor et al. U.S. Pat. No. 4,442,843 and Rasor et al., U.S. Pat. No. 4,681,119) describe the use of contrast media to enhance ultrasonic images of a number of liquid-filled regions of the body, such as those of the reproductive system.
Others have disclosed the use of an intrauterine catheter containing a contrast medium in conjunction with a diagnostic scanning device. For example, Eden, U.S. Pat. No. 4,349,033 issued Sep. 14, 1982, discloses a method of providing a fluid to the interior of a body cavity, such as woman's uterus, while scanning with an ultrasonic transducer. Visualization of pelvic structures, the Fallopian tubes, ovaries and the cul-de-sac is said to be improved. The technique is described as allowing a doctor to detect the presence of a pelvic mass, abnormal vaginal bleeding, pelvic cancer staging, congenital anomalies or pelvic infections.
Two investigators have described the use of an ultrasound contrast medium to evaluate the condition of Fallopian tubes. Unger, U.S. Pat. No. 5,230,882 issued Jul. 27, 1993, discloses a general method for imaging a patent using ultrasound comprising administering to the patient a liposome contrast medium and scanning the patient using an ultrasound device. In a nonvascular application, the liposomal contrast medium may be injected directly into the area to be scanned, such as into the uterine cavity to assess "patency" of the Fallopian tubes. According to the second investigator, in the second document, Soviet Union Patent Document No. 1323082, published Jul. 15, 1987, "uterine tube patency" may be diagnosed by filling the tubes with a spasmolytic solution, followed by ultrasound visualization. However, there is no disclosure of using ultrasound during pregnancy, let alone a teaching of applicability to the placenta.
As to the use of an ultrasound contrast medium during pregnancy for other purposes, Finberg et al., in an article entitled "Definitive Prenatal Diagnosis of Monoamniotic Twins: Swallowed Amniotic Contrast Agent Detected in Both Twins on Sonographically Selected CT Images", J Ultrasound Med (1991) 10:513-16, describes the diagnosis of the potentially dangerous condition of monoamniotic twinning at 27 weeks. This diagnosis was by the detection, on sonographically selected computed tomographic ("CT") images, of intestinal opacification in each twin after a single injection of the contrast medium into the amniotic space. FIGURE 1 of the publication, which appears to be a conventional sonogram without the use of contrast media, is described as showing the positions where the umbilical cords of both twins insert into the placenta and the absence of a detectable intervening amniotic membrane. When a single amniocentesis is performed to inject a contrast medium into the amniotic fluid, which is then swallowed by each twin, the ultrasound-selected CT images showed concentrated contrast medium in the intestine of each twin, confirming that they were monoamniotic. When this condition was confirmed, labor was induced to deliver the twins prematurely to prevent catastrophic events due to the knotting of intertwined loops of the two umbilical cords sharing the same amniotic sac.
However, there is no teaching in Finberg et al. of how to evaluate the condition of the placenta itself, or the volume of blood flowing through the placenta, even in this environment, much less in instances of apparently normal pregnancies.
The literature in this area can thus be divided roughly into two groups: (1) the use of ultrasound contrast media to assess the condition of various body cavities, such as parts of the reproductive system, for example, the uterus, Fallopian tubes and/or vagina; (2) and the use of ultrasound scanning with a contrast medium during pregnancy to confirm a suspected diagnosis of monoamniotic twins.
Moreover, those working in the art have not proposed the use of contrast media to facilitate the ultrasound assessment of the condition of the placenta itself during pregnancy. The use of contrast media for direct observation of the fetus has generally been ruled out as involving an undue risk, particularly in monitoring what is an apparently healthy pregnancy. Those working in the ultrasound art have expressly avoided fetal-prenatal vascular studies altogether due to the prevailing fears of introducing complications during pregnancy.
Therefore, there remains a need for a method to study maternal intervillous and related placental blood flow that allows for a measure of uteroplacental circulation. In this way, it is proposed that poor placentation can be detected at a sufficiently early stage to attempt treatment.